PROJECT SUMMARY/ABSTRACT Metabolic syndrome, characterized by hypercholesterolemia, hypertriglyceridemia, hypertension, hyperglycemia and insulin resistance, has become a major health risk in modern society, and are a leading cause of death. Among current anti-atherosclerosis medications, Statins and Niacins increase blood glucose and reduce insulin resistance, making them a high risk for patients with diabetes. Ezetimibe and bile acid sequestrants do not work as well as Statins. Thus, there is a need for new safe and effective drugs to combat this devastating disease. Our previous studies demonstrated that amlexanox, an inhibitor of IKK? and TBK1, increases insulin sensitivity and improves glucose metabolism. Recent preliminary data have shown that amlexanox also attenuates diet-induced atherosclerosis in Ldlr-/- mice. Hypercholesterolemia, systemic chronic inflammation and aortic cells dysfunction are three major causes of atherosclerosis. Our current study has indicated that amlexanox improves hypercholesterolemia, attenuates monocytosis and prevents aortic cell dysfunctions. RNA-seq analysis of liver demonstrated that amlexanox increases expression of genes involved in bile acid synthesis and secretion, which may explain how amlexanox reduces blood cholesterol. Based on this preliminary data, we hypothesize that amlexanox protects Ldlr-/- mice from Western diet (WD)-induced atherosclerosis by increasing cholesterol excretion, reducing inflammation and attenuating aortic cell dysfunction. The goals for this proposal are to thoroughly assess the anti-atherosclerosis effects of amlexanox, and uncover the underlying mechanisms. Specific Aim 1 will evaluate the effects of amlexanox on cholesterol metabolism, which include its absorption, excretion and biosynthesis. Specific Aim 2 will identify a transcription factor that mediates amlexanox-induced expression of bile acid synthesis genes, and investigate how amlexanox regulates activity of the transcription factor. Specific 3 will assess effects of amlexanox on proliferation of hematopoietic stem and progenitor cells (HSPCs) and functions of endothelial cells and smooth muscle cells to explain how amlexanox exerts its effects on monocytosis and aortic cell dysfunction. The career goal for the applicant is to become a highly competitive candidate for an independent assistant professor position by gaining additional expertise in the study of cholesterol metabolism and atherosclerosis. The outstanding research environments and available resources at UCSD, along with the experts serving on candidate?s advisory committee will provide exemplary support for the applicant to achieve his career goal. Furthermore, the candidate?s primary mentor has an exceptional record in successful transitioning trainees to independent assistant professors. With the support of the K99/R00 award, the candidate will be well positioned to compete for a tenure track faculty position.